The present invention relates to a method for the preparation of a controlled release system and especially to a method for entrapment of compounds in polymer carriers for controlled release of active ingredients, preferably bioactive ingredients, such as drugs. This method results in a system for controlled release of active ingredients and especially for controlled drug delivery. In accordance with the present invention, the term “controlled release” encompasses all kinds of controlled release, including slow release, sustained and delayed release. Particularly, the present invention results in active ingredients, entrapped in or otherwise incorporated in or coupled to polymer carriers or polymeric devices, such as micelles, nanoparticles, microspheres, hydrogels and other types of polymer carriers or devices for controlled release; the active ingredients are bonded to, and especially covalently bonded to the polymeric devices or carriers.
Nanoparticulate polymeric carriers such as micelles, are considered to be promising candidates for the targeted delivery of drugs. These systems may be constructed so as to have a so-called enhanced permeation and retention effect in a variety of diseased areas. Such polymeric devices for the targeted delivery can contain a broad variety of bioactive ingredients, among which hydrophobic drugs.
In this light, reference can be made to U.S. Pat. No. 7,425,581 and EP-A-1 776 400, describing micelles based on hydrophobically modified PEG-polymethacrylamide block copolymers. These polymers display a unique combination of temperature sensitivity and biodegradability, which provide easy drug loading and controlled release properties, respectively, to the micelles.
Moreover, it was demonstrated by Rijcken et al. in Biomaterials 28 (2007), 5581-5593 that cross-linking of, i.e. the covalent conjugation of, polymers in a micellar core, was essential to realise a long blood circulation of the micelles after intravenous administration in mice. In addition, they found that empty cross-linked micelles accumulate to a 6-fold higher extent in tumor tissue when compared with non-cross-linked micelles.
However, non-covalent (physical) encapsulation of drugs, or other active ingredients, in polymeric micelles (or other devices) often results in the rapid loss of the active ingredients, especially after being applied to the system where the active ingredients are intended to achieve their activity, such as in vivo. This is due to rapid drug diffusion and/or to premature disintegration of the carrier. Although this latter mechanism can be prevented or at least retarded by cross-linking the micelles, the non-covalently entrapped drug compounds in these cross-linked micellar cores were prone to burst release immediately after introduction in the human of animal body, such as by intravenous injection. This rapid release from the stabilised micelles is the result of drug diffusion.
In addition, it was found that the properties of the micelles containing non-covalently entrapped drugs, as described in said U.S. Pat. No. 7,425,581 and EP-A-1 776 400, are detrimentally affected as a result of aggressive processing, for example freeze-drying. Especially in medical applications and in particular in drug delivery applications, good storage stability of the drug-loaded particles is important. The present invention aims to provide methods for providing long term product stability of drug delivery systems, for instance by lyophilisation (freeze-drying).
In the prior art, methods have been developed for covalent encapsulation of drugs. In covalent encapsulation, active ingredients such as drug molecules are chemically bonded to the polymer chains. These polymers can be hydrophilic and consequently, such systems are termed polymer-drug conjugates that can be administered as such. Alternatively, the polymer can be amphiphilic and in an aqueous environment, micelles are formed which can be administered as such. Such types of micelles may, upon intravenous administration, suffer from stability problems, leading to a disintegration into the separate components. The polymer modification can be done for example by using organic synthesis.
Ulbrich et al. describe in an article in J. Contr. Rel. 87 (2003), 33-47, a water soluble HPMA copolymer conjugated with the anticancer drug doxorubicin. Doxorubicin is attached to the polymer carrier via a hydrolytically labile spacer containing either a hydrazone bond or cis-aconitic acid residue.
Conjugates with hydrolytically-releasable doxorubicin are also described by Ríhová et al. in J. Contr. Rel. 74 (2001), 225-232, and Ková et al. in J. Contr. Rel. 99 (2004) 301-314.
A polymer micelle carrier system for doxorubicin is described by Nakanishi et al. in J. Contr. Rel. 74 (2001) 295-302. First, doxorubicin is conjugated to a block copolymer of polyethylene glycol and polyaspartic acid. Next, a micelle carrier system is formed by dissolving this modified polymer in an aqueous environment. This carrier system additionally encompasses free (physically entrapped) doxorubicin.
In Panarin et al., Pharmaceutical Chemistry Journal 23, (1989), 689-694, derivatives of glucocorticoids are disclosed which are derivatised with water-soluble polymers. In particular, it is disclosed that hydrocortisone, prednisolone or dexamethasone is acylated by a copolymer of vinylpyrrolidone with maleic anhydride to form polyesters of said glucocorticoids.
Covalent bonding of drug molecules can also be done by the copolymerisation of polymerisable drug derivatives upon polymer synthesis. In Davaran et al., J. Contr. Rel. 58 1999, 279-287, drug-containing monomers are free radically copolymerized with methacrylic acid or hydroxyethyl methacrylate. The acrylic polymer backbone bears the drug units as side substituents attached through hydrolysable bonds, such as ester or amide bonds.
Disadvantages of these known systems are the necessity to perform organic synthesis to couple the drug molecules to high molecular weight polymer chains (with consequent challenges), and the necessity to develop a new polymer for each drug molecule which limits the applicability of a new polymer platform technology. In addition, in polymer-drug conjugates mainly water-soluble polymers are used for covalent bonding of drug molecules, thereby often limiting the application of these polymer-drug conjugates to water-soluble drugs. Moreover, hydrophilic polymer-drug conjugates are less stable in aqueous solution as these remain in contact with the aqueous solution and, thus, easily degrade.